Oncogenic genomic alterations in cancer are excellent therapeutic targets. Compelling clinical examples include somatic mutations in the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC), BRAF mutations in melanoma, and BCR-ABL translocations in chronic myeloid leukemia. In all instances, potent and selective kinase inhibitors have demonstrated significant clinical activity and are currently the therapeutic standard of care. Improvements in technology coupled with sequencing of the human genome, has led to identification of rare cancer subsets that harbor clinically significant oncogenic alterations. Rearrangements of the anaplastic lymphoma kinase (ALK) occur in ~ 3% of NSCLC patients. Crizotinib, an ALK inhibitor, is clinically efficacious in ALK rearranged NSCLC and was specifically approved as a therapy for this genetically defined subset of cancer patients in just 4 years after its initial discovery. This rapid progress, from discovery to clinical implementation, has been aided by systematic genotyping of cancer patients, now routine at many institutions including at the DFCI. RET is transmembrane receptor tyrosine kinase that is normally expressed in cells derived from neural crest and the urogenital tract. It is mutated in ~ 50% of medullary thyroid cancer (MTC) and rearranged in ~35% of papillary thyroid cancer. In addition, RET mutations underlie the familial cancer syndromes multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN 2B) and familial medullary thyroid cancers. Vandetinib, a multitargeted kinase inhibitor that also inhibits RET, is an approved therapy for MTC based on a phase III clinical trial. We recently identified a rearrangement in RET (KIF5B-RET) in a subset of NSCLC patients. This fusion gene is oncogenic in vitro and the transformed cells are sensitive to multi-targeted kinase inhibitors that inhibit RET. Thus RET inhibitors may also be clinically effective in this population of NSCLC patients. Here we propose critical studies that will inform the clinical deployment of RET inhibitors such as investigating the cancer biology of oncogenic forms of RET, studying the incidence of RET alterations in lung cancers and developing strategies to identify patients for clinical studies. Furthermore, none of the kinase inhibitors currently approved that inhibit RET, or in clinical development, are specific inhibitors of RET. Thus the development of more potent and selective RET inhibitors will likely have therapeutic implications for the treatment of patient with both thyroid and NSCLC harboring genomic alterations in RET. We plan to achieve these goals through the following specific aims. Aim 1: To establish the oncogenic properties of RET; Aim 2: To develop novel inhibitors of RET that possess the potency, selectivity, and pharmacological properties that will enable their use in cellular and in vivo models; Aim 3: To develop and evaluate in vivo strategies to treat cancers harboring genomic alterations in RET. Findings from these studies have therapeutic implications for patients with cancers harboring genomic alterations in RET and catalyze the development of clinical trials for such patients.